Enhancing tissue penetration of physiologically active steroidal agents with dmso

ABSTRACT

A method of enhancing tissue penetration of physiologically active steroidal agents by conjointly applying them to the tissue with dimethyl sulfoxide. Penetration of the skin and the mucous membranes of the body cavities by these agents may be enhanced by cojoint application of such agents and dimethyl sulfoxide directly to such membranes. Preferably, for penetration of these agents through the skin compositions of DMSO at concentrations of 50 percent and above are employed and for penetration through mucous membranes, compositions including DMSO at concentrations of 10 percent and above are employed. Steroidal Agents may be advantageously administered by injection with DMSO in concentrations preferably up to 20 percent by weight to enhance penetration of internal tissue membranes barriers to achieve better distribution of these agents.

United States Patent [1 1 Herschler l l ENHANCING TISSUE PENETRATION OFPHYSIOLOGICALLY ACTIVE STEROIDAL AGENTS WITH DMSO [75] lnvcntor: RobertJohn Wash.

Herschler, Camus,

[73] Assignee: Crown Zellerbach Corporation, San

Francisco, Calif.

[22] Filed: Sept. 2, 1970 [21] Appl. No.: 69,155

Related U.S. Application Data [63] Continuation-impart of Ser. No.753,231, Aug. 16,

1968, Pat. No. 3,551,554, which is a continuation-inpart of Ser. No.329,l5 l Dec. 9, I963, abandoned.

[52] U.S. Cl ..424/243, 424/337 [51] Int. Cl. ..A6lk 17/00 [58] Field ofSearch ..424/243, 337

[56] References Cited UNITED STATES PATENTS 2,942,008 6/1960 Lubowe..252/364 2,936,3l3 5/1960 Elks et al ..260/397.45 3,045,033 7/1962Gould et al ..260/397.45

3,l90,855 6/1965 Miki ..260/63 3,472,93l l0/l969 Stoughton ..424/l 80FOREIGN PATENTS OR APPLICATIONS l,l73 ll/l965 Ireland OTHER PUBLlCATlONSFaust American Perfumer 77(l):23-26, Jan. 1962, Some New Components forCosmetic and Dermatologic Vehicles.

11] 3,711,606 1 Jan. 16, 1973 Primary Examiner-Shep K. RoseAtt0rney-Corwin R. Horton and Robert E. Howard [57] ABSTRACT A method ofenhancing tissue penetration of physiologically active steroidal agentsby conjointly applying them to the tissue with dimethyl sulfoxide.Penetration of the skin and the mucous membranes of the body cavities bythese agents may be enhanced by cojoint application of such agents anddimethyl sulfoxide directly to such membranes. Preferably, for

penetration of these agents through the skin compositions of DMSO atconcentrations of 50 percent and above are employed and for penetrationthrough mucous membranes, compositions including DMSO at concentrationsof IO percent and above are employed.

Steroidal Agents may be advantageously administered by injection withDMSO in concentrations preferably up to 20 percent by weight to enhancepenetration of internal tissue membranes barriers to achieve betterdistribution of these agents.

9 Claims, No Drawings ENHANCING TISSUE PENETRATION OF PIIYSIOLOGICALLYACTIVE STEROIDAL AGENTS WITH DMSO CROSS REFERENCES TO RELATEDAPPLICATION This is a continuation-in-part of co-pending applicationSer. No. 753,231, filed Aug. 16, 1968, now U.S. Pat. No. 3,551,554 datedDec. 29, 1970 and which is, in turn, a continuation in part ofapplication Ser. No. 329,15 1 filed Dec. 9, 1963, now abandoned.

BACKGROUND OF THE INVENTION A predominant and limiting problem in thedevelopment and use of physiologically active agents is the inability toadminister them as effectively as is desired. In particular, there isoften a limitation as to the routes of administration because of thefollowing factors:

1. Some agents are inactivated in the gastrointestinal tract or they areabsorbed poorly into the body from the tract. Also, undesireable sideeffects may result which prevent effective oral administration.

2. In every case where injection must be resorted to, there is a risk ofneedle injury, infection and other trauma (including the emotionaltrauma inevitably associated with injections).

3. Few agents are absorbed through the skin or mucous membranes ineffective quantities and the rate of absorption is less than would bedesirable for those that do.

4. A local concentration for a local effect is often desired but alarger systemic dose must be given to achieve an effective concentrationat the local area when the agent can only be injected or given orally(but not topically). This higher dose often causes undesirable sideeffects, since dosage-related side effects are very prevalent for manyagents.

Animal tissues comprise various membranes which are selectivelypermeable and which allow some substances to pass freely, whilerejecting others or permitting only slight passage. Such membranescomprise the body coverings and externally communicating cavities,including the skin and mucous membranes of the body cavities, e.g.alimentary tract, respiratory tract, genitourinary tract, oral cavity,eyes, etc. (collectively defined herein as external membranes). Theyalso include internal membranes such as the linings of the variousorgans and other internal body structures, e.g. peritoneum and pleura,and the membranes surround ing cellular and intracellular structures. Itis desirable in overcoming the aforementioned problems in drugadministration to increase the passage or penetration of agents acrosssuch membranes and further to enhance their intercellular andintracellular diffusion in order for them to reach their situs ofactivity more rapidly to achieve the desired response more quickly andoften more effectively. It is exceptionally desirable to do this in areversible manner, by which is meant penetration of the agents in tissuewithout adversely affecting or impairing the function or structure ofthe tissue. It is known that certain substances will penetrate tissueonly after the tissue has been irreversibly damaged, which is certainlyundesirable. Certain agents, such as surfactants, have been knownpreviously for increasing penetration of various agents. However, againsuch penetration was effected only through irreversible damage of thetissue.

It has been a major rule in medicine that the vehicles" or carriers"have relatively little effect on the penetration rate for a given agentand this rule generally still holds true. Thus, with conventionalcarriers for medicines, such as alcohol, carbowax, water, etc., fewagents will adequately penetrate such formidable external membranebarriers as the intact skin or mucous membrane. It is to be expectedthat this would be true of all potential vehicles or materials combinedwith physiologically active agents. However, surprisingly, it has beendiscovered that dimethyl sulfoxide (DMSO) 'has the unusual ability togreatly enhance the penetration of agents when they are applied to suchmembrane barriers along with dimethyl sulfoxide. The penetration ofagents which previously have not penetrated these membranes to aneffective degree may be enhanced sufficiently so that a useful resultmay be obtained. The penetration of agents which have been known topenetrate to a limited degree in conventional vehicles may besignificantly enhanced. New and convenient routes of administration,often with a decrease in side effects of the agents, better localizedconcentration and a more sustained activity, may thereby be created formany agents.

In my co-pending application Ser. No. 615,377, filed Feb. 13, 1967, isdisclosed my related discovery that DMSO enhances the penetration ofplant-active agents (pesticides, dyes, nutrients, hormones, herbicidesand the like) into plant tissue in a highly unusual manner.

Dimethyl sulfoxide is a water-white liquid at room temperature having afreezing point of approximately l8.5C. and a specific gravity ofapproximately 1.1. Dimethyl sulfoxide is a well known industrial solventand it has been available in commercial quantities for at least a decade(from Crown Zellerbach Corporation, San Francisco, Calif). DMSO wasoriginally synthesized in 1866 and since that time it has beenextensively investigated for possible industrial and biological utilityand a considerable amount of literature has developed on its propertiesand uses. Over the last 25 years it has found widespread use as asolvent in industry and in the laboratory.

DMSO has been investigated in the past for various biochemical uses, forexample as a reaction solvent for preparing derivatives of variousproteins and antibiotics, as an extraction solvent for various proteins,as an analytical solvent and as a solvent for various other laboratoryuses. It has also been suggested as a solvent for certain pesticides(see, for example, U.S. Pat. No. 3,068,142).

DMSO has been investigated as a preservative agent for in vitro storageof chilled or frozen tissue and it has also been determined to have aprotective effect in experimental animals subjected to X-irradiationfollowing injection of DMSO into such animals.

In connection with topical application of the antifungal griseofulvin,DMSO has been listed along with various inert materials as bland, highboiling fliuds to be used as carriers for the griseofulvin in applyingit to the skin to control fungus growth in the skin (see British PatentNo. 810,377). DMSO has been employed as a solvent for preparation ofcertain injectable formulations, namely chloramphenicol and ananthelminic preparation (see US. Pat. 3,067,096).

Despite the employment of DMSO as a solvent for these purposes anddespite general experimentation with DMSO in the medical field, theunique ability of DMSO to alter membrane permeability and to therebyenhance penetration of physiologically active agents was neithersuggested nor discovered. Although DMSO has been a well known and widelyinvestigated solvent for many years, its unique ability to enhancepenetration of external and internal membrane barriers as contemplatedin the present invention has been totally unrecognized.

My co-pending application Ser. No. 753,231 is directed to utilizing DMSOto enhance penetration of various categories of physiologically activeagents, including antineoplastic agents, antigens, antihistaminicagents, neuropharmacologic agents, diagnostic dyes and radiopaque agentsand nutrients. Many of these categories are unrelated to steroids butsome, such as antinoeplastic agents and antiinflammatory agents,comprehend the various steroids having the indicated physiologicalactivity. The present application is directed specifically tophysiologically active steroids inclusive of those steroids havingactivities falling within the categories of my co-pencling applicationand those that do not.

Nos. 3,044,936 and SUMMARY OF THE lNVENTION By a mechanism or mechanismsnot yet fully understood, DMSO, when applied to animal tissue, increasesthe permeability of the tissue in a reversible manner to cause a muchgreater penetration rate for conjointly applied physiologically activeagents, and specifically steroids. Although the mode of activity isstill unclear, it is definitely not that of the simple vehicle orcarrier since the effect may be obtained to some extent even when theDMSO is applied to tissue separately and the enhanced penetrability ofthe tissue may last for as much as three hours after the DMSO treatment.

When applied to the intact skin along with dimethyl sulfoxide,particularly at a DMSO concentration of 50 percent by weight and above,or to skin pretreated with the dimethyl sulfoxide, a steroid maypenetrate rapidly to and saturate the stratum corneum (the highlyresistant horny layer" of the skin which is the major barrier topenetration). The steroid continues to penetrate through the skin fromthis "reservoir" in the stratum corneum to the underlying tissue andinto the circulatory system.

Similarly, penetration into underlying tissues and into the circulatorysystem may be obtained from topical application to the mucous membranesof the body cavities as in the case of intraoral, conjuctival sac,rectal, vaginal and bladder instillation administration, particularlywhere the DMSO is utilized at a concentration of percent by weight andabove. It is thus seen that a particularly important aspect of thisinvention is that penetration of agents, and specifically steroids, maybe effectively enhanced following topical administration. As used inthis connection herein, the term topical" is intended to includeapplication to all external membrane barriers, including the cutaneousor epidermis regions and the mucous membranes, including thegastrointetinal tract, the respiratory tract and the genitourinarytract.

important advantages are also obtained through the injection routes forphysiologically active steroidal agents. When these agents are injectedinto the tissues either in a composition including dimethyl sulfoxide(preferably at DMSO concentrations exceeding 1 percent and especially inthe range of 10 20 percent by weight) or together with conjoint butseparate application of DMSO to the tissues, the effect is an enhancedand more even distribution thereof into the tissues surrounding theinjection site compared with conventional injection techniques. Thismore even distribution is of considerable advantage for both local andsystem effect for all of the usual injectable routes, e.g. subcutaneous,intramuscular, intraperitoneal, etc.

Where a local effect is desired, the intimatedistribution of thesteroidal agent in the tissue near the site of injection prolongs andenhances its physiologic activity at this local site. This may permituse of a lower dose to achieve the desired response with a smaller riskof side effects which may result from a higher close.

For all routes of administration, conjoint application of DMSO alongwith physiologically active steroidal agents having an activity site inthe individual cells of the host may additionally result in an enhancedeffect of the agent through the ability of DMSO to increase thepermeability of such individual cells to such agents;

As previously indicated, the mechanisms of penetration enhancement areas yet not fully elucidated. Accordingly, it is not believed that DMSOacts by several mechanisms in enhancing penetration. DMSO is believed toact directly on tissue toalter the general permeability of the tissuemembrane. More specifically, DMSO when applied thereto is believed todecrease the natural resistance of tissue membranes to penetration byforeign agents. DMSO is also believed to promote penetration by a directtransport effect, perhaps by the mechanism of complexing with the agent.This mechanism is believed more applicable to cationic and anionicagents.

GENERAL DESCRIPTlON OF THE INVENTION This invention is applicable to thetissue or organisms of all animal phyla, DMSO having differing degreesof influence onpenetration of various tissue types of a given animal.Animals of particular importance in the practice of the invention arethe mammalians, especially man and veterinary animals. However, theinvention may also be practiced with other vertebrates, as for examplethe amphibians, fishes, reptiles, etc., and with the lower speciescomprising the non-vertebrates.

As indicated previously, a measure of penetration enhancement may beobtained where the tissue is pretreated with DMSO prior to applicationthereto of the physiologically active steroidal agent. The tissuepenetrability is thus altered by such pretreatment and this reversibleeffect gradually diminishes and the tissue returns to its normalpermeability state. However, for convenience and optimal effect, it isfrequently desirable to administer the DMSO and the agent simultaneouslyin the same composition.

Penetration enhancement is generally non-selective in terms of the typeor physiological effect or effects of agents to be transported acrossmembrane barriers.

The extent of penetration enhancement will depend upon many factors, thepredominant factors being the relative natural permeability of theparticular membrane, the concentration of DMSO applied, the extent ofsolubility of the agent in DMSO and the chemical and physical propertiesof the agent.

The size of the compound obviously may influence to some extent therelative ability of steroidal agents to penetrate tissue. However,effective membrane penetration utilizing DMSO has been demonstrated forextremely large compounds, for example compounds having molecularweights exceeding 40,000. Even for such a formidable membrance barrieras intact human skin, quite large compounds have been demonstrated to beeffectively enhanced.

Standard occlusion techniques frequently may increase the percutaneousabsorption of the larger molecules. In general, at least a limiteddegree of solubility of the agent in DMSO is desirable to achievemaximum benefit of the present invention. Naturally, the practitionerwill select steroidal agents, routes of administration and compositionforms guided by these well known principles.

Steroids are generally classed as organic molecules which have in commona perhydrocyclopentanophenanthrene nucleus and they are so named becausethey are related to and usually derived from sterols found abundantly innature in animal and plant fats. Certain steroids are naturally producedin the body and they act as hormones to mediate and control many bodyfunctions. These hormones have been isolated or produced syntheticallyand used in replacement therapy for hormone deficiencies. Additionallyand importantly, these steroids have been found to be highly usefuldrugs in the treatment of a wide range of disease states not primarilydue to lack of hormones. ln the recent past, extensive research efforthas resulted in the synthesis of a vast number of new steroid hormonederivatives having biological activity (in excess of 1,500 compounds)and the list is growing rapidly. Such derivatives usually containmodifying groups ,linked to the steroid as by modifying, prolonging orincreasing its activity, increasing stability and/or modifying itssolubility characteristics. These modifying groups usually compriseaddition salts to influence solubility of a side chain substitution onone or more reactive ring carbon atoms. The side chain may be a directsubstitution for a ring hydrogen, an ester formed at a reactive hydroxylgroup or an ether group. Many of these steroid derivatives have a higherpotency than the naturally occurring steroid hormones, often with adecrease in the undesirable side effects which frequently result fromadministration of the natural steroids. As used herein, the termsteriods" and steroidal agents" is intended to comprehend both thenatural steroids and the biologically active modifications, derivativesand equivalents.

Steroid drugs may have one or more of many types of biological activitysuch as anabolic, androgenic, glucocorticoid, mineralocorticoid,estrogenic, progestogenic, lipoidiatic (removal of stored fat),circulatory system activity, central nervous system activity,anti-cancer and anti-osteroporic, Some steroid drugs have the ability toblock the activity of other hormones, including the activity of othersteroids. Their biological activity may be characterized asantiandrogenic, antiglucocorticoid, antimineralocorticoid (diuretic),antiestrogenic and antiprogestogenic. The term physiologically active indescribing steroidal agents herein is intended to comprehend all ofthese and any other useful activities. Various activities will beconsidered hereinafter in connection with specific embodiments of thisinvention.

The concentration of the DMSO applied to enhance penetration may varyover wide limits. The concentration selected is desirably related to theroute of administration to be employedv For cutaneous application,compositions including at least about 50 percent by Weight DMSO arepreferable in that they have been found to increase percutaneouspenetration in a highly significant manner. Maximum cutaneouspenetration is generally attained with DMSO concentrations closelyapproaching 100 percent (excluding the agent), but with concentrationsmuch above percent by weight the incremental increase in penetrationrate over that achieved at 90 percent often is relatively small. On theother hand, above a 90 percent concentration of dimethyl sufoxide, theside effects of a burning sensation and erythema increase significantly.Accordingly, for topical use, it may be desirable, consistent withphysical stability of the composition, to formulate the DMSO incompositions containing a DMSO concentration of between about 50 percentand 90 percent by weight and containing water, preferably 10 percent byweight or greater.

Application to mucous membranes follows generally the procedure forcutaneous administration. However, lower concentrations of DMSO, forexample as low as l0 percent by weight, may be preferred sincepenetration of mucous membrane is more easily affected.

For most injection routes, preferably lower concentrations of DMSO ofabout 10 percent to about 20 percent by weight are utilized. For someinjection routes, for example intraand peri-articular routes, higherconcentrations, say 30-40 percent, may be preferred.

The amount of the physiologically active steroidal agent to beadministered will obviously be an effective amount for the desiredresult expected therefrom. This, of course, will be ascertained by theordinary skill of the practitioner. Due to enhanced activity which maybe achieved through better penetration, the dosage of agent may often bedecreased from that generally applicable. In accordance with the usualprudent formulating practices, a dosage near the lower end of the usefulrange of the particular agent may be employed initially and the dosageincreased as indicated from the observed response, as in the routineprocedure of the physician.

As previously discussed, the DMSO may advantageously be compounded withthe physiologically active steroidal agent for concurrentadministration. The usual pharmaceutical compounding agents, diluents orcarriers may be included in these compositions as desirable for theparticular route of administration and dosage form. The amount and typeof diluent or carrier used should, of course, be consistent with thecompatability of the agent in DMSO and the diluent. A co-solvent, orother standard adjuvant such as a surfactant may be called for tomaintain the agent in solution or suspension at the desiredconcentration. Where stability of the agent in the presence of DMSO atthe agent, obviously the known toxicity, side effects and ef- Ifectiveness for a given route of administration should be taken intoaccount. For example, due to skin irritation known to be caused by someagents or due to poor penetration characteristics, some other route thandermal application may be the route of choice for such agents.

Dosage forms for topical application may include solutions (paints),nasal sprays, lotions, ointments (including creams and gels),suppositories and the like. The solutions and nasal sprays may simplycomprise the agent dissolved in DMSO, optionally with an amount ofwater, glycerine or other diluent. For nasal sprays and other mucousmembrane applications, isotonic saline may be preferable as a diluent.The DMSO may be present in these forms in various concentration, sayfrom about 10 percent to about 75 percent by weight or higher.

Lotions and gels, ointments or creams may contain the usual ingredientsto provide a base, as for example cetyl alcohol, an emulsifier such aslauryl sulfate, and water. Another base may be formulated by combiningequal weight amounts of stearic acid, cetyl alcohol, triethanolamine andglycerol monostearate with water. Still other bases may utilizepolyethylene glycols of different viscosities, depending upon thedesired consistency. DMSO may be added to the lotion or ointment base invarying amounts as desired, generally up to around 50 percent by weight.

A suppository form may be made from a high viscosity polyethylene glycol4,000, water and DMSO, which may be present in an amount of aboutpercent by weight.

The concentration of physiologically active steroidal agent in thevarious dosage forms is, of course, commensurate with that normallyutilized for the particular agent in conventional formulations foreffective results for the intended route. Both the amount ofphysiologically active steroidal agent and the amount of DMSO will beinfluenced by the type of effect desired. If a more localized effect isrequired, as for example in treating a skin condition, lower amounts ofphysiologically active steroidal agent and lower concentrations of DMSOmay be called for. Where deeper penetration is desired, a higherconcentration of DMSO may be desirable to promote adequate penetration.Where general systemic concentration of an agent is desired for atopical preparation, generally higher concentrations of DMSO aredesirable and the amount of steroidal agent may be included in thecomposition sufficient to provide the blood level desired.

The various pharmaceutical forms are desirably provided in determinedamounts, as in containers of a given volume. These amounts may include100 percent DMSO concentration containing the desired dose of the agent,or a lesser concentration of DMSO with a diluent and the physiologicallyactive agent dose. Thus, for example, graduated ampules containing, say,5 cc. of 100 percent DMSO with the agent dissolved therein may beprovided. The practitioner need only open and dispense all or adetermined part to a subject. Nasal spray bottles, aspirators,suppositories, cotton tipped stick applicators, squeeze tubes may all beutilized for topical application.

The following illustrates the practice of the present invention withvarious classes of steroidal agents.

DESCRIPTION OF PREFERRED EMBODIMENTS GLUCOCORTICOIDS Hormones producednaturally in the body by the adrenal cortex are called adrenal corticalsteroids or corticoids. Some corticoids, predominantly cortisone andhydrocortisone, have the property of influencing the rate of metabolismof glucose. Hence they, along with their derivatives and modifications,are called glucocorticoids. Glucocorticoids have other predominantphysiologic activity which makes them highly useful as;

drugs. One of the most important activities is the suppression ofinflammation, particularly in the treatment of arthritis and rheumaticdiseases. Glucocorticoids are also useful in the treatment ofdermatoses, drug reactions, bronchial asthma, lupus erythematosus,angioneuroedema and many other disorders. Massive doses ofcorticosteroids have also been used to induce remissions in leukemia.Glucocorticoids are generally, 3-keto, A 4, l l-oxygen function (hydroxyor keto), 20- keto steroids of the pregnane series. Typically they alsohave a 2l-hydrogen, halogen or hydroxy function. The ll-hydroxyglucocorticoids are of particular interest for local application withDMSO due to their ability to induce local effects. DMSO may be combinedwith glucocorticoids to enhance their penetration to the affected tissuefor these variousdisorders. The following examples illustratecompositions and treatments for this purpose utilizing the mostprominent and active natural and modified glucocorticoids.

EXAMPLE I Penetration of Injected Corticosteroids A 32 year old whitewoman was seen with ,a 2 days history of left subdeltoid bursitis. Thisgave her pain on minimal abduction particularly, but also was present inother movements of the shoulder joints. Physical examination revealedmarked tenderness to pressure with obvious protective muscle spasmoverlying the joint. Two ml of hydrocortisone was injected into thebursal area. This was associated with 3 hours relief of pain. Thepatient was seen again 2 days later. At this examination her pain wasjust as marked as the first visit. Two ml. of hydrocortisone wasinjected and 5 cc. of percent dimethyl sulfoxide was applied liberallyto the entire left shoulder area. Within 15 minutes all pain disappearedand the patient reported no return of her symptoms when examined 1 weeklater.

Example 2 Penetration of Injected Corticosteroids.

A 42 year old white male was examined with'a 1 week history of acutesubdeltoid bursitis of the right shoulder. Four mg. of Decadron wasinjected into the right subdeltoid bursa. The patient estimated thatabout a 20 percent relief of his discomfort was attained.

Full pain returned 1 day later. At this point he was reinjected with 4mg. of Decadron and 4 cc. of 100 percent dimethyl sulfoxide was placedon the skin over the involved bursa. This time the pain disappearedcompletely and did not recur.

Both of the above examples show that cortisone injected for subdeltoidbursitis is obviously of benefit, but that its relief of symptomatologyis enhanced with the simultaneous application of dimethyl sulfoxide tothe skin.

Example 3 Penetration of Corticosteriods A 24 year old medical studentwas seen with atopic dermatitis of the right antecubital fossa. Threecc. of 100 percent dimethyl sulfoxide was applied four times daily for 3days. No benefit was noted. One mg. or onefourth cc. of Decadron(dexamethasone Zl-phosphate) was applied four times a day for 2 dayswithout benefit. One mg. of dexamethasone ZI-phosphate in 3 cc. of 100percent dimethyl sulfoxide was painted onto the involved area four timesdaily for 3 days. At the end of this period all evidence of theinflammatory reaction had disappeared.

This example shows an improved action of dexamethasone 2l-phosphate whenused with dimethyl sulfoxide.

Example 4 The following lotion formulation may be prepared containingabout 0.01 to 1.0 percent, and preferably 0.l percent fluocinoloneacetonide:

Fluocinolone acetonide 0.1-1.0 gm Cetyl alcohol 200 gm Propylene glycolgm Sodium lauryl sulfate gm DMSO 300 gm Water qs 1000 cc The steroid isdissolved in the DMSO and added to a stirred, cooling melt of the otheringredients. The preparation is particularly useful for the treatment ofinflamed dermatoses by topical application to the affected skin area.The amount and frequency of application is in accordance with standardpractice for topical application of this steroid. Penetration of thesteroid into the inflamed tissue in enhanced and a therapeutic level isachieved more rapidly than when the steroid is applied in conventionalformulations.

Example 5 The following ointment (gel) formulation may be preparedcontaining about 0.2 percent to L0 percent, and preferably 0.6 percenttriamcinalone acetonide:

Triamcinalone acetonide 0.2-l0 gm Polyethylene glycol 400 400 gmDimethyl sulfoxide 598 gm Carboxy vinyl polymer powder I grnTriethanolamine 0.4 gm

The corticosteroid is dissolved in a mixture of the first twoingredients and the carboxy vinyl polymer gelling agent is sprinkled onthe surface of the combined liquids and stirred until all the particleshave been wetted and dispersed. The triethanolamine is then addeddropwise to the mixture until it has gelled, care being taken tominimize the air entrapment. This gel is particularly effective in thetreatment of seborrhea and other scalp and hair inflammatory conditionsand may be applied in amount and frequency conventionally used fortopical application of this steroid. Better penetration and thereby anincreased anti-inflammatory active is obtained for the amount of steroidapplied than results from its application in conventional formulations.

Example 6 The following ointment formulation may be prepared containingabout 0.1 percent to 1.0 percent prednisone and preferably 0.5 percent:

Prednisone 0.1-l0 gm Glyceryl monostearate, I gm acid type Stearylalcohol 50 gm Polysorbate 80 20 cc Water 450 cc Dimethyl sulfoxide 300cc The product is prepared as described in Example 4. The ointment is avaluable base for application of the corticosteroid to inflammatorydermatological areas, particularly when they require inunction.Application is in accordance with that usual for topical application ofthis steroid in conventional bases.

Example 7 The following cream formulations may be prepared containingabout 0.1 percent to 1 percent 16a-methyl prednisolone and preferably0.5 percent:

l6a-methyl prednisolone 0.l-l0 gm Stearic acid 200 gm Glycerylmonostrearate, 200 gm acid type Sodium lauryl sulfate 20 gm Dimethylsulfoxide 200 gm Water qs 1000 cc As above, the product is prepared asdirected in Example 4 and is useful in severe dermatoses requiringinunction.

What I claim is:

1. A method of enhancing the penetration into and across an externalmembrane barrier of a human or animal subject of a physiologicallyactive glucocorticoid steroidal agent capable of eliciting aphysiological effect upon topical application thereof, which comprisesthe concurrent topical administration to the external membrane of anamount of said steroidal agent effective to produce the desiredphysiological effect and an amount of DMSO sufficient to effectivelyenhance penetration of said steroidal agent to achieve the desiredphysiological effect.

2. A method as in claim 1 and wherein the said agent is applied to theintact skin in a composition which includes said DMSO and wherein theDMSO in said com position is at least about 50 percent by weight of thecomposition.

3. A method as in claim 1 and wherein said agent is applied to induce atleast a physiological effect locally to the site of application.

tion contains a pharmaceutically acceptable thickening agent in anamount sufficientvto materially increase the viscosity thereof, wherebyto facilitate topical application.

8. A method as in claim 7 wherein said composition is in the form of anointment.

9. A method as in claim 7 and wherein said composition is in the form ofa lotion.

2. A method as in claim 1 and wherein the said agent is applied to theintact skin in a composition which includes said DMSO and wherein theDMSO in said composition is at least about 50 percent by weight of thecomposition.
 3. A method as in claim 1 and wherein said agent is appliedto induce at least a physiological effect locally to the site ofapplication.
 4. A method as in claim 1 and wherein said glucocorticoidis a 3-keto, Delta 4, 11-oxygen function, 20-keto steroid of thepregnane series.
 5. A method as in claim 4 and wherein saidglucocorticoid is a 11-hydroxy steroid.
 6. A method as in claim 1 andwherein said agent is applied to said membrane in a composition whichincludes said DMSO.
 7. A method as in claim 6 and wherein saidcomposition contains a pharmaceutically acceptable thickening agent inan amount sufficient to materially increase the viscosity thereof,whereby to facilitate topical application.
 8. A method as in claim 7wherein said composition is in the form of an ointment.
 9. A method asin claim 7 and wherein said composition is in the form of a lotion.